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Information on EC 1.14.19.69 - biflaviolin synthase and Organism(s) Streptomyces coelicolor and UniProt Accession Q9FCA6

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IUBMB Comments
This cytochrome-P-450 (heme-thiolate) enzyme, from the soil-dwelling bacterium Streptomyces coelicolor A3(2), catalyses a phenol oxidation C-C coupling reaction, which results in the polymerization of flaviolin to form biflaviolin or triflaviolin without the incorporation of oxygen into the product [1,3]. The products are highly conjugated pigments that protect the bacterium from the deleterious effects of UV irradiation .
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Streptomyces coelicolor
UNIPROT: Q9FCA6
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The taxonomic range for the selected organisms is: Streptomyces coelicolor
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
hide
2
flaviolin
+
2
reduced ferredoxin [iron-sulfur] cluster
+
2
H+
+
O2
=
3,8'-biflaviolin
+
2
oxidized ferredoxin [iron-sulfur] cluster
+
2
H2O
2
+
2
reduced ferredoxin [iron-sulfur] cluster
+
2
+
=
+
2
oxidized ferredoxin [iron-sulfur] cluster
+
2
2
flaviolin
+
2
reduced ferredoxin [iron-sulfur] cluster
+
2
H+
+
O2
=
3,3'-biflaviolin
+
2
oxidized ferredoxin [iron-sulfur] cluster
+
2
H2O
2
+
2
reduced ferredoxin [iron-sulfur] cluster
+
2
+
=
+
2
oxidized ferredoxin [iron-sulfur] cluster
+
2
Synonyms
cyp158a2, cyp158a1, cytochrome p450 158a2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
CYP 158A2
-
-
-
-
cytochrome P450 158A2
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
flaviolin,reduced ferredoxin:oxygen oxidoreductase
This cytochrome-P-450 (heme-thiolate) enzyme, from the soil-dwelling bacterium Streptomyces coelicolor A3(2), catalyses a phenol oxidation C-C coupling reaction, which results in the polymerization of flaviolin to form biflaviolin or triflaviolin without the incorporation of oxygen into the product [1,3]. The products are highly conjugated pigments that protect the bacterium from the deleterious effects of UV irradiation [1].
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
4 flaviolin + 4 reduced ferredoxin [iron-sulfur] cluster + 4 H+ + O2
3,3'-biflaviolin + 3,8'-biflaviolin + 4 oxidized ferredoxin [iron-sulfur] cluster + 4 H2O
show the reaction diagram
CYP158A2 produces three isomers of biflaviolin and one triflaviolin
-
-
?
2-hydroxy-1,4-naphthoquinone + reduced ferredoxin [iron-sulfur] cluster + H+ + O2
? + oxidized ferredoxin [iron-sulfur] cluster + H2O
show the reaction diagram
-
-
about 70fold lower activity than with flaviolin
-
?
4 flaviolin + 4 reduced ferredoxin [iron-sulfur] cluster + 4 H+ + O2
3,3'-biflaviolin + 3,8'-biflaviolin + 4 oxidized ferredoxin [iron-sulfur] cluster + 4 H2O
show the reaction diagram
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
4 flaviolin + 4 reduced ferredoxin [iron-sulfur] cluster + 4 H+ + O2
3,3'-biflaviolin + 3,8'-biflaviolin + 4 oxidized ferredoxin [iron-sulfur] cluster + 4 H2O
show the reaction diagram
CYP158A2 produces three isomers of biflaviolin and one triflaviolin
-
-
?
4 flaviolin + 4 reduced ferredoxin [iron-sulfur] cluster + 4 H+ + O2
3,3'-biflaviolin + 3,8'-biflaviolin + 4 oxidized ferredoxin [iron-sulfur] cluster + 4 H2O
show the reaction diagram
isoform CYP158A1 can only produce 3,3'-biflaviolin and 3,8'-biflaviolin with quite different molar ratios compared with the products from CYP158A2
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P450
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-
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4-phenylimidazole
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crystallization data. Presence of malonic acid affects binding behaviour and increases inhibitory potency up to 2fold
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0073 - 0.0432
flaviolin
0.0105 - 0.0169
flaviolin
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.017
flaviolin
-
pH 7.5, 37°C
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
I87K mutant of isoform CYP158A2, hanging drop vapor diffusion method, using 0.1 M bis-Tris (pH 6.5), 1.2 M ammonium dihydrogen phosphate
complex of ferric CYP158A2 with substrate analogue 2-hydroxy-1,4-naphthoquinone, 2.15 A resolution, and the flaviolin ferrous dioxygen-bound CYP158A2 complex, to 1.8 A resolution. In the ferrous dioxygen-bound flaviolin complex, the three water molecules in the ferric flaviolin complex still occupy the same positions and form hydrogen bonds to the distal dioxygen atom. A continuous hydrogen-bonded water network connecting the active site to the protein surface is proposed to participate in the proton-delivery cascade, leading to dioxygen bond scission
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free enzyme and in complex with flaviolin, diffration to 1.75 and 1.62 A resolution, respectively.Upon ligand binding, a major conformational change takes place that closes the entry into the active site, partly due to repositioning of the F and G helices. Presence of two molecules of flaviolin in the closed active site that form a quasi-planar three-molecule stack including the heme
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free isoform CYP158A1, in complex with imidazole and in complex with flaviolin. Comparison of structures with isoform CYP158A2. In isoform CYP158A1, only one flaviolin molecule is present close to the heme iron, and the second flaviolin molecule binds at the entrance of the putative substrate access channel on the protein distal surface 9 A away
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in complex with inhibitor 4-phenylimidazole, crystallization in presence of malonic acid. Diffraction to 1.5 A resolution. Presence of malonic acid affects binding behaviour and increases inhibitory potency up to 2fold. Two molecules of malonate are found above the single inhibitor molecule in the active site, linked between the BC loop and beta 1-4/beta6-1 strands via hydrogen bond interactions to stabilize the conformational changes of the BC loop and beta strands that take place upon inhibitor binding. 4-Phenylimidazole can launch an extensive hydrogen-bonding network in the region of the F/G helices which may stabilize the conformational changes
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
I87K
mutant of isoform CYP158A2, the mutation significantly changes the ratios of the dimerization products converting CYP158A2 into a CYP158A1-like monooxygenase
K90I
mutant of isoform CYP158A1, the catalytic activity of the mutant does not change at all compared with the wild type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni2+ affinity chromatography and S-Sepharose/Q-Sepharose column chromatography
Ni2+ affinity chromatography and S-Sepharose/Q-Sepharose column chromatography
recombinant protein
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 (DE3) pLysS cells
expressed in Escherichia coli BL21 (DE3) pLysS cells
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Zhao, B.; Waterman, M.R.; Isin, E.M.; Sundaramoorthy, M.; Podust, L.M.
Ligand-assisted inhibition in cytochrome P450 158A2 from Streptomyces coelicolor A3(2)
Biochemistry
45
7493-7500
2006
Streptomyces coelicolor, Streptomyces coelicolor A3(2)
Manually annotated by BRENDA team
Zhao, B.; Lamb, D.C.; Lei, L.; Kelly, S.L.; Yuan, H.; Hachey, D.L.; Waterman, M.R.
Different binding modes of two flaviolin substrate molecules in cytochrome P450 158A1 (CYP158A1) compared to CYP158A2
Biochemistry
46
8725-8733
2007
Streptomyces coelicolor
Manually annotated by BRENDA team
Zhao, B.; Guengerich, F.P.; Bellamine, A.; Lamb, D.C.; Izumikawa, M.; Lei, L.; Podust, L.M.; Sundaramoorthy, M.; Kalaitzis, J.A.; Reddy, L.M.; Kelly, S.L.; Moore, B.S.; Stec, D.; Voehler, M.; Falck, J.R.; Shimada, T.; Waterman, M.R.
Binding of two flaviolin substrate molecules, oxidative coupling, and crystal structure of Streptomyces coelicolor A3(2) cytochrome P450 158A2
J. Biol. Chem.
280
11599-11607
2005
Streptomyces coelicolor, Streptomyces coelicolor A3(2)
Manually annotated by BRENDA team
Zhao, B.; Guengerich, F.P.; Voehler, M.; Waterman, M.R.
Role of active site water molecules and substrate hydroxyl groups in oxygen activation by cytochrome P450 158A2: a new mechanism of proton transfer
J. Biol. Chem.
280
42188-42197
2005
Streptomyces coelicolor
Manually annotated by BRENDA team
Zhao, B.; Bellamine, A.; Lei, L.; Waterman, M.
The role of Ile87 of CYP158A2 in oxidative coupling reaction
Arch. Biochem. Biophys.
518
127-132
2012
Streptomyces coelicolor (Q9FCA6), Streptomyces coelicolor (Q9KZF5), Streptomyces coelicolor A3(2) (Q9FCA6), Streptomyces coelicolor A3(2) (Q9KZF5), Streptomyces coelicolor A3(2)
Manually annotated by BRENDA team